A Comparative Analysis of Lymphocyte Subpopulations in Patients on Natalizumab, Fingolimod, and Dimethyl Fumarate

Background: The oral disease modifying therapies fingolimod and dimethyl fumarate are known to decrease lymphocyte counts and like natalizumab have been associated with risk of infectious complications – prompting consideration of surveillance of these numbers in some cases. New therapies that affect specific populations of such cells continue to emerge in multiple sclerosis (MS) and their short- and long-term effects on the immune system need further investigation.

Objectives: The goal of this study is to examine the impact of disease-modifying therapies on lymphocyte subpopulations over time to better inform monitoring  on therapies in MS patients and best practice.

Methods: In this study, the lymphocyte profiles of 56 patients on either natalizumab, fingolimod, or dimethyl fumarate were examined retrospectively. Selection criteria included  diagnosis of MS and 3-month duration on the therapy studied. Subpopulations analyzed included CD3 (normal range 900-3245), CD4 (560-1840), CD8 (260-1230), CD4/CD8 ratio (0.9-3.4), and total T-lymphocytes (1000-4800). Unpaired, two-tailed t-tests were used for comparative analyses of each drug on specific cell lines. Significance was determined with p<0.05.

Results: Natalizumab did not have a significant effect on any of the three lymphocyte subsets, with only minor fluctuations in the normal ranges over a period of up to four years. However, fingolimod and dimethyl fumarate had substantial effects on the three cell lines studied when compared to natalizumab. Both fingolimod (µ: 462), and dimethyl fumarate to a lesser extent (µ: 1090), significantly lowered CD3 counts. Similarly, while both were significant, fingolimod lowered CD4 and CD8 (µ: 269, 134) more than dimethyl fumarate (µ: 780, 264). However, the magnitude of the CD8 decrease for dimethyl fumarate was proportionally greater than its impact on CD4. The opposite was true for finglimod, affecting CD4 more than CD8. Therefore, dimethyl fumarate significantly increased CD4/CD8 ratios (µ: 3.89) while fingolimod significantly decreased CD4/CD8 ratios (µ: 1.43). This differential effect on the CD4/CD8 ratio was also upheld over time with CD4/CD8 ratios diverging for dimethyl fumarate and fingolimod. Overall, total lymphocyte counts were significantly reduced for fingolimod (µ: 896) and dimethyl fumarate (µ: 2178) compared to natalizumab (µ: 3320).

Conclusions: With significant decreases observed in all three cell lines studied in patients on fingolimod and dimethyl fumarate, these data reveal the impact that therapies may have on lymphocyte counts and the nature of the changes. The differential impact of each new MS therapy on specific cell lines can inform risk management and  changes in therapy. Further considerations of understanding this information may help to inform a particular drug’s mechanism of action and may also have implications regarding which cells are driving a patient’s disease for tailoring therapy in the future.